Controlled release potassium chloride tablet

ABSTRACT

A pharmaceutical dosage form is prepared from a multiplicity of coated potassium chloride crystals coated with two distinct layers, the first of ethylcellulose and the second of a hydrophilic coating polymer, preferably hydroxypropylcellulose, resulting in microcapsules. These microcapsules are capable of being compressed into tablets of suitable hardness and friability with minimum quantities of excipients. The resultant controlled release tablets are useful for treatment of potassium deficiencies in humans.

BACKGROUND OF THE INVENTION

The present invention pertains to an improved controlled releasepotassium chloride tablet and a process for its preparation. Moreparticularly, the present invention relates to a potassium chloridetablet prepared from microcapsules of potassium chloride crystals coatedwith two distinct layers, the first of ethylcellulose and the second ofa hydrophilic polymer, preferably hydroxypropylcellulose. Thesemicrocapsules are capable of being compressed into tablets of suitablehardness and friability with minimum compression and quantities ofexcipients.

Sustained release formulations consisting of microencapsulatedpharmaceutical agents coated with a single layer composed ofethylcellulose have been disclosed. Anderson, et al. disclose aspirincoated with a single layer of ethylcellulose (U.S. Pat. No. 3,341,416).Miller, et al. disclose a process for coating aspirin crystals with asingle layer of polymeric material, such as ethylcellulose (U.S. Pat.No. 3,155,590). Tamas discloses a process for the preparation ofsustained release solid pharmaceutical compositions which containcrystals of an active ingredient coated with a single layer of a polymersuch as ethylcellulose (U.S. Pat. No. 4,748,023). Lippman, et al.disclose a controlled release capsule containing potassium salt coatedwith ethylcellulose and external surfactant having an HLB in excess of10 (U.S. Pat. No. 4,259,315).

Other standard controlled release formulations consisting ofmicroencapsulated pharmaceutical agents coated with a single layer of apolymer mixture have been disclosed. Bechgaard, et al. disclose acontrolled release tablet or capsule with contains a core comprising anactive agent and coated with a diffusion membrane which is insoluble ingastrointestinal fluids which may include ethylcellulose (U.S. Pat. No.4,193,985). Samejima, et al. disclose the coating of microcrystals witha single layer consisting of a polymer mixture, such as ethylcelluloseand hydroxymethylcellulose (U.S. Pat. No. 4,462,982). Pedersen, et al.disclose a controlled release composition containing a core of activeagent which may be potassium chloride coated with a water insoluble, butwater diffusible, layer consisting of a mixture of a solvent, afilm-forming substance which may be ethylcellulose, and a hydrophobicsubstance (U.S. Pat. No. 4,572,833). Roswell, et al. disclose acontrolled release composition containing a core of active agent whichmay be potassium chloride coated with a water insoluble, but waterdiffusible, layer consisting of a mixture of a solvent, a film-formingsubstance which may be ethylcellulose, and a hydrophobic substance withparticles of the active agent adhered to the coating (U.S. Pat. No.4,574,080). Hsiao discloses a sustained release dosage form ofquinidine-coated pellets coated with a single layer which consists of amixture of ethylcellulose and hydroxypropylcellulose (U.S. Pat. No.4,634,587). Snipes discloses controlled release potassium chloridecrystals coated with a single layer of a two component polymer mixturewhich consists of 85-97% ethylcellulose and 3-15% of an amphiphile (U.S.Pat. No. 4,832,955). Hsiao, et al. disclose a controlled releasepotassium chloride tablet form for oral administration which containspotassium chloride crystals coated with a single layer which consists ofa mixture of ethylcellulose and either hydroxypropylcellulose orpolyethylene glycol (U.S. Pat. No. 4,863,743).

Still other sustained release formulations consisting ofmicroencapsulated pharmaceutical agents coated with a plurality ofpolymeric coatings have been disclosed. Zeitoun, et al. disclosecompressed tablets for disintegration in the colon which contain a coreof an active ingredient and a two-layer coating, the inner coating whichmay be of ethylcellulose controls the diffusion of the active ingredientand an enteric outer coating of an organic polymer (U.S. Pat. No.4,432,966). Kjornaes, et al. disclose a sustained release tablet whichcontains crystals of the active ingredient coated with an inner layer ofan aqueous dispersion of a film-forming agent which causes adhesionbetween the crystals at elevated temperatures and an outer layer of awater-based, film-forming agent which prevents adhesion of the crystalsduring heating, imparting flowability (U.S. Pat. No. 4,716,041).

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method of preparingethycellulose microencapsulated potassium chloride crystals with acoating of a hydrophilic polymer which allows compression into tabletsof suitable hardness and friability at low compaction pressures whencombined with a minimum amount of excipients and having controlleddissolution characteristics.

Another object is to provide tablets comprised of the treatedmicroencapsulated potassium chloride crystals and excipients, wherein anamount of excipients lower than that conventionally used allowsmanufacture of tablets containing a minimum quantity of excipientsrelative to the quantity of treated microencapsulated potassiumchloride, thereby providing a single tablet which can deliver aneffective daily dosage of potassium without being unduly large forswallowing.

A further object is to provide tablets comprised of treatedmicroencapsulated potassium chloride and excipients which disintegraterapidly when administered orally, thereby releasing themicroencapsulated potassium chloride for rapid disintegration in thegastrointestinal tract and controlled dissolution, reducing thelikelihood of localized toxicity and damage to the gastric mucosa.

A still further object is to provide a method of treating, relieving, orpreventing potassium deficiency in humans with minimal adverse sideeffects comprising orally administering tablets comprised of aneffective amount of ethylcellulose microencapsulated potassium chloridecoated with a hydrophilic polymer and a minimum quantity of excipients.

Additional objects will become apparent hereinafter and still otherobjects will be apparent to one of ordinary skill in the art from thefollowing disclosure.

These and other objects are accomplished according to the presentinvention which provides an improved controlled release potassiumchloride tablet prepared from a multiplicity of potassium chloridecrystals coated with two distinct layers, the first of ethylcelluloseand the second of an least one hydrophilic polymer, preferablyhydroxypropylcellulose, resulting in microcapsules. These microcapsulesare capable of being compressed into tablets of suitable hardness andfriability with minimum quantities of excipients and without disruptionof the ethylcellulose rate controlling membrane.

DETAILED DESCRIPTION OF THE INVENTION

A plurality of potassium chloride crystals, preferably from about 20mesh to about 70 mesh, more preferably from about 30 mesh to about 50mesh, are coated with two distinct layers. The first layer applied tothe crystals is composed of ethylcellulose, preferably with a viscosityof from about 90 to about 110 cp. such as Ethocel 100 (Dow Chemical).Utilization of this high viscosity ethylcellulose allows the crystals toretain their diffusion controlling characteristics even aftercompression into a tablet form. The ethylcellulose may be applied by anysuitable technique known in the art, preferably by coacervation usingpolyethylene as a phase separator. If coacervation is used, traceamounts of the phase separator may be present in the first layer,preferably in an amount less than about one percent by weight of theethylcellulose coated crystals. The ethylcellulose layer comprises fromabout 8 to about 19.5 percent, more preferably from about 11 to about 15percent, of the total weight of the uncoated potassium chloridecrystals. This first layer controls the release of the potassiumchloride over time, total release time being proportionally dependentupon the thickness of ethylcellulose. After application of theethylcellulose, a drying step should preferably be carried out for sucha time period and at such temperatures so that the microencapsulatedcrystals do not adhere to other microcapsules. The resultantethylcellulose encapsulated potassium chloride microcapsules arepreferably of such a size that less than 5% are greater than 20 mesh.

A second, discrete layer of at least one hydrophilic polymer coating,preferable a hydroxypropylcellulose, such as Klucel LF (AqualonCompany), is applied over the first layer of ethylcellulose. Otherhydrophilic polymer coatings include, but are not limited to, polyvinylalcohol, polyvinyl pyrrolidone, and hydroxypropyl methylcellulose. Thehydrophilic layer is applied by conventional techniques, such as from anaqueous solution using a fluidized bed coater, to the preformed layer ofethylcellulose. The hydrophilic polymer coating layer comprises fromabout 0.5 to about 4 percent, more preferably from about 0.5 to about1.5 percent, of the weight of the ethylcellulose coated crystals. Thehydrophilic polymer does not significantly diffuse into theethylcellulose, but rather forms a distinct second layer. As this layeris soluble to gastric fluids, the hydrophilic polymer coating dissolvesfollowing ingestion of the resultant tablet. For all practical purposes,it does not contribute to the controlled release of potassium chloride.Rather, the hydrophilic polymer coating is present primarily as a bindermaterial so that a high dosage rate tablet can be formed with a minimalamount of conventional excipients and low compaction pressures to allowminimal disruption of the rate controlling ethylcellulose membrane.

After the hydrophilic polymer coating layer is applied, the now doublecoated crystals are subjected to a final drying step The resultantcoated potassium chloride microcapsules are preferably of such a sizethat less than 15% are greater than 20 mesh. The coated crystals maythen be formed into tablets by compression using conventionaltechniques. A minimal amount of excipients, no more than about 15% morepreferably no more than 12%, and most preferably no more than 7%, byweight of the final dosage tablet, is added to the coated crystals priorto compression. This is in contrast to the greater than 30% excipientstypically necessary for compression of potassium chloride microcapsuleswithout a hydrophilic coating layer into a tablet form. In addition,this formulation allows the microencapsulated potassium chloride to bedispersed essentially intact over a wide area, reducing the risk ofgastric irritation.

The term "excipients", as used herein, refers to any additionalpharmaceutically acceptable ingredients which may be used in a tablet.These excipients include, but are not limited to, ingredients such asbinders, disintegrants, wetting agents, and lubricating agents. Bindersinclude, but are not limited to, Klucel® LF (hydroxypropylcellulose) andAvicel® (microcrystalline cellulose). Disintegrants include, but are notlimited to, cornstarch, lactose, mannitol, sucrose, Avicel®(microcrystalline cellulose), Primogel® (sodium carboxymethyl starch,Emcompress® (dibasic calcium phosphate dihydrate), Crospovidone® (crosslinked polyvinyl pyrrolidone), and tricalcium phospate. Wetting agentsinclude, but are not limited to, sodium lauryl sulfate. Lubricatingagents include, but are not limited to stearates (e.g. magnesium,calcium, and sodium,) stearic acid, Sterotex®, talc waxes, andStearowet®.

The final tablets will contain a pharmaceutically acceptable amount ofpotassium chloride to treat humans in need thereof, preferably fromabout 8 mEq to about 20 mEq. Acceptable daily dosages may be found inThe Physicians' Desk Reference, 45th ed. (1991), e.g. 20-200 mEq/day.

EXAMPLES Example 1

The coated potassium chloride microcapsules of the present invention maybe produced by coacervation as follows:

    ______________________________________                                        Ingredient               Amount                                               ______________________________________                                        Potassium Chloride, USP  567    kg                                            Cyclohexane              875    gal                                           Ethylcellulose, NF       83.5   kg                                            Polyethylene             58     kg                                            Hydroxypropyl Cellulose, NF                                                                            6.9    kg                                            Purified Water, USP      35     kg                                            ______________________________________                                    

The potassium chloride, cyclohexane, ethylcellulose, and polyethyleneare mixed together with controlled agitation and heating until thepolymers are in solution. The solution is then cooled to achieveencapsulation of the potassium chloride with the ethylcellulose. Theresulting microcapsule slurry is next filtered using a rotary vacuumfilter and the resulting wet microcapsules are dried in a fluidized beddrier. The dry microcapsules are sized, preferably through a 14 meshsieve to produce potassium chloride microcapsules ready for coating.

A solution of hydroxypropylcellulose and purified water is prepared. Thepotassium chloride microcapsules are coated with this solution using afluidized bed coater. The resulting coated microcapsules are then driedand sized through a 12 mesh sieve.

By the foregoing technique, other hydrophilic polymers which provide abinding effect may be used, ie. polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropyl methylcellullose, which have foundacceptance in coating pharmaceuticals.

Example 2

The release rate of the microcapsules of Example 1 were measured usingthe USP Basket Method, 900 ml purified water, 100 rpm at 37 degrees C.

    ______________________________________                                        Release Rate (%/hour)                                                         Time (hours)                                                                              Trial 1     Trial 2 Trial 3                                       ______________________________________                                        1           21.8        17.6    15.0                                          4           71.3        57.6    54.7                                          8           99.5        92.1    89.6                                          ______________________________________                                    

Example 3

The microcapsules of Example 1 are used to prepare 20 mEq potassiumchloride tablets using conventional tabletting techniques, e.g.compressed on an instrumented rotary tablet press, and conventionaltabletting excipients, e.g. binders, disintegrants, wetting agents, andlubricating agents. The release rate of the potassium chloride tabletswere measured using the USP Basket Method, 900 ml purified water, 100rpm at 37 degrees C.

    ______________________________________                                        Release Rate (%/hour)                                                         Time (hours)                                                                              Trial 1     Trial 2 Trial 3                                       ______________________________________                                        1           21.4        22.0    17.0                                          2           40.0        36.9    33.2                                          4           71.6        65.1    60.8                                          6           90.2        87.3    84.5                                          8           99.4        101.3   97.4                                          ______________________________________                                    

Example 4

The coated potassium chloride microcapsules of Example 1 were made intotablets using conventional tabletting techniques and the followingformulation:

    ______________________________________                                        Ingredient            Percent                                                 ______________________________________                                        Coated KCL microcapsules                                                                            88                                                      Microcystalline cellulose                                                                           10                                                      Cross-linked polyvinyl pyrrolidone                                                                   2                                                      ______________________________________                                    

The potassium chloride microcapsules of Example 1 were also preparedwithout the hydroxypropylcellulose coating or any other hydrophilicpolymer coating. These uncoated microcapsules could not be made intotablets using conventional tabletting techniques and the aboveformulation. The amount of KCl microcapsules in the formulation had tobe decreased to about 68% in order that they might be tabletted usingconventional tabletting techniques.

The above description is for the purpose of teaching the person ofordinary skill in the art how to practice the present invention and isnot intended to detail all those obvious modifications and variations ofit which will become apparent to the skilled worker upon reading thedescription or to limit the invention in any way. It is intended,however, that all such obvious modifications and variations be includedwithin the scope of the present invention and by the following claims.

What is claimed is:
 1. A process for preparing a controlled release tablet of potassium chloride comprising:(a) microencapsulating crystals of potassium chloride with an inner layer of ethylcellulose to form microcapsules; (b) coating said microcapsules with an outer layer comprising at least on hydrophilic polymer to form coated microcapsules; (c) drying said coated microcapsules; (d) adding at lease one excipient to said dried, coated microcapsules; and (e) compressing said dried, coated microcapsules and said at lease one excipient into a tablet.
 2. The process of claim 1, wherein the hydrophilic polymer comprises hydroxypropylcellulose.
 3. The process of claim 1, wherein the hydrophilic coating comprises polyvinyl alcohol.
 4. The process of claim 1, wherein the excipients comprise not more than about 15% by weight of said tablet.
 5. The process of claim 1, wherein the excipients comprise not more than about 12% by weight of said tablet.
 6. The process of claim 1, wherein the excipients comprise not more than about 7% by weight of said tablet.
 7. The process of claim 1, wherein said ethylcellulose has a viscosity between about 90 cp. and about 110 cp.
 8. The process of claim 1, wherein said ethylcellulose comprises between about 8 and about 19.5 percent by weight of said crystals.
 9. The process of claim 1, wherein said ethylcellulose comprises between about 11 and about 15 percent by weight of said crystals.
 10. The process of claim 2, wherein said hydroxypropylcellulose comprises about 0.5 to about 4 percent by weight of said microcapsules.
 11. The process of claim 2, wherein said hydroxypropylcellulose comprises about 0.5 to about 1.5 percent by weight of said microcapsules.
 12. The sustained release tablet prepared by the process of claim 1 add wherein the excipient amount is no more than about 15%.
 13. The sustained release tablet prepared by the process of claim 1 and wherein the excipient amount is no more than about 12%.
 14. The sustained release tablet prepared by the process of claim 1 and wherein the excipient amount is no more than about 7%.
 15. The tablet of claim 12, wherein the potassium chloride is in an amount effective to treat potassium deficiency of a human.
 16. The tablet of claim 12, wherein the amount of potassium chloride is from about 8 to about 20 mEq.
 17. A method of treating potassium deficiency in humans be oral administration of the table of claim
 12. 